Abstract The increasing rates of obesity and diabetes highlight the need to understand the brain circuits and cellular mechanisms regulating energy balance and glucose homeostasis. Prominent among these is the central leptin- melanocortin system, which includes the pro-opiomelanocortin (POMC) neurons, subsets of which express leptin receptors (LEPRs). Understanding how leptin differentially regulates energy balance versus glucose homeostasis is key for the development of anti-obesity and anti-diabetes therapies. Early observations based on prenatal genetic manipulations led to the widely-held model that LEPR-expressing POMC neurons mediated the metabolic actions of leptin, however, evidence now suggests that these pathways are more complex than originally anticipated. The current application extends our early developmental models by directly testing the role of leptin action in adult melanocortin neurons in regulating glucose metabolism and responding to dynamic challenges, including fasting and cold exposure. We also have in hand a model in which liver insulin resistance can be induced in a temporal manner, allowing us to investigate the role of the leptin- melanocortin pathway in its development. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine, autonomic, and behavioral functions, particularly at the level of adipose tissues and liver.